Evidence map›Paper›PMID 38811818›Full record

ArticleLeukemia2024

Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition.

Ruiqi Zhu, Courtney M Shirley, S Haihua Chu, Li Li, Bao H Nguyen, Jaesung Seo, Min Wu, Tessa Seale, Amy S Duffield, Louis M Staudt and 3 more

Abstract read
PubMed Publisher
In one paragraph

Article in Leukemia, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Ruiqi Zhu *Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Courtney M Shirley *Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
S Haihua ChuDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Li LiDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bao H NguyenDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jaesung SeoDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Min WuDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Tessa SealeDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Amy S DuffieldDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Louis M StaudtLymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Mark LevisDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0003-0473-6982
Yu HuDepartment of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.ORCID 0000-0002-2815-4568
Donald SmallDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. donsmall@jhmi.edu.ORCID 0009-0006-3410-7000

Funding

Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) P30 Ca06973Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R01 CA90668Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) T32 CA60441National Natural Science Foundation of China (National Science Foundation of China) 822000187
6 · The paper itself

Abstract

Internal tandem duplication mutations of FLT3 (FLT3/ITD) confer poor prognosis in AML. FLT3 tyrosine kinase inhibitors (TKIs) alone have limited and transient clinical efficacy thus calling for new targets for more effective combination therapy. In a loss-of-function RNAi screen, we identified NOTCH4 as one such potential target whose inhibition proved cytotoxic to AML cells, and also sensitized them to FLT3 inhibition. Further investigation found increased NOTCH4 expression in FLT3/ITD AML cell lines and primary patient samples. Inhibition of NOTCH4 by shRNA knockdown, CRISPR-Cas9-based knockout or γ-secretase inhibitors synergized with FLT3 TKIs to kill FLT3/ITD AML cells in vitro. NOTCH4 inhibition sensitized TKI-resistant FLT3/ITD cells to FLT3 TKI inhibition. The combination reduced phospho-ERK and phospho-AKT, indicating inhibition of MAPK and PI3K/AKT signaling pathways. It also led to changes in expression of genes involved in regulating cell cycling, DNA repair and transcription. A patient-derived xenograft model showed that the combination reduced both the level of leukemic involvement of primary human FLT3/ITD AML cells and their ability to engraft secondary recipients. In summary, these results demonstrate that NOTCH4 inhibition synergizes with FLT3 TKIs to eliminate FLT3/ITD AML cells, providing a new therapeutic target for AML with FLT3/ITD mutations.

Indexed as

fms-Like Tyrosine Kinase 3Leukemia, Myeloid, AcuteProtein Kinase InhibitorsReceptor, Notch4Xenograft Model Antitumor AssaysAnimalsCell Line, TumorDrug Resistance, NeoplasmHumansMiceMutationSignal TransductionFLT3 protein, humanfms-Like Tyrosine Kinase 3NOTCH4 protein, humanProtein Kinase InhibitorsReceptor, Notch4

Identifiers

PMID38811818

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.